Calix[4]arenes bearing α-amino- or α-hydroxyphosphonic acid fragments at the upper rim

Article abstract of DOI:10.1002/hc.2

By the reaction of para-formylcalix[4]arenes 1-6 with trialkyl phosphites in the presence of dry hydrogen chloride, calix[4]arenes 7-13 possessing dialkylphosphoryl-hydroxymethyl groupings at the upper rim were synthesized. Calix[4]arenes 18-23 functional

Full text of DOI:10.1002/hc.2

Heteroatom Chemistry
Volume 12, Number 2, 2001
Calix[4]arenes Bearing ␣-Amino- or
␣-Hydroxyphosphonic Acid Fragments at
the Upper Rim
Andrew Solovyov,1 Sergey Cherenok,1 Ivan Tsymbal,1
Salvatore Failla,2 Giuseppe A. Consiglio,3 Paolo Finocchiaro,3
and Vitaly Kalchenko1
1Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Murmanskaya str. 5,
02094 Kiev-94, Ukraine
2Dipartimento di Ingegneria Chimica, dei Materiali, delle Materie Prime e Metallurgiche, Universita`
di Roma “La Sapienza,” Via del Castro Laurenziano 7, I-00161 Rome, Italy
3Istituto Chimico, Facolta di Ingegneria, Universita di Catania, Viale A. Doria 6, I-95125 Catania,
Italy
Received 19 October 2000; revised 16 November 2000
self-assembly with formation of dimeric OH•••OסP
ABSTRACT: By the reaction of para-formylca-
hydrogen bonded associates. ᭧ 2001 John Wiley &
lix[4]arenes 1–6 with trialkyl phosphites in the pres-
Sons, Inc. Heteroatom Chem 12:58–67, 2001
ence of dry hydrogen chloride, calix[4]arenes 7–13
possessing dialkylphosphoryl-hydroxymethyl group-
ings at the upper rim were synthesized. Calix[4]arenes
18–23 functionalized with dialkylphosphoryl-al-
kyl(aryl)aminomethyl groups were obtained by so-
dium-promoted addition of dialkyl phosphites to CסN
bonds of para-iminocalix[4]arenes 14–17.
The consecutive treatment of ␣-hydroxy- or ␣-ami-
nophosphonic acid dialkyl esters of calix[4]arenes 7,
10, 18, and 21 with bromotrimethylsilane and meth-
anol gave dihydroxyphosphoryl derivatives of ca-
lix[4]arenes 24–27.
It was shown that calix[4]arenes bearing at the
macrocyclic upper rim hydroxymethylphosphonic
fragments, as well as bis-hydroxymethyl(amino-
methyl)phosphonic fragments, are able to undergo
INTRODUCTION
The calixarenes are a group of phenolic macrocyclic
compounds that play a significant role in supramo-
lecular chemistry [1,2]. This interest is connected
with the ability of calixarenes to bind organic and
inorganic species with formation of host-guest-type
complexes [3]. The latter are stabilized by noncova-
lent interactions (coulombic, dipole-dipole forces,
CH-p, solvatophobic interactions, etc.) [4,5], which
play an important role in biochemical processes. Ca-
lixarenes can also mimic natural enzyme action [6]
and serve as lipophilic containers for the transport
of a bioactive guest through cell membranes [7]. One
of the most important routes to the synthesis of new
bioactive compounds consists of functionalization
of the calixarene skeleton with fragments of natural
or artificial biologically active compounds [8–11].
␣-Hydroxy and ␣-aminophosphonic acid deriv-
Correspondence to: Paolo Finocchiario and Vitaly Kalchenko.
Contract Grant Sponsor: INTAS-Ukraine Programme.
Contract Grant Number: 95/0129.
Contract Grant Sponsor: INCO-COPERNICUS.
Contract Grant Number: IC15-CT98-0298.
᭧ 2001 John Wiley & Sons, Inc.
58

Calix[4]arenes Bearing ␣-Amino- or ␣-Hydroxyphosphonic Acid Fragments at the Upper Rim 59
atives being metabolites of natural aminoacids [12],
lix[4]arenes 18–23 were in the range of 60–65%
(Scheme 2).
are known to belong to the class of bioactive com-
pounds. These compounds inhibit specifically some
fermentative reactions [13] and possess high cancer-
ostatic, bacteriostatic, and cytotoxic activity [13,14].
In our previous paper, we described a convenient
synthetic procedure for insertion of ␣-hydroxy and
␣-aminophosphonic acid dialkyl ester fragments at
the upper rim of a macrocycle [15]. It was shown
that mono- and bis-(dialkylphosphoryl-hydroxy-
methyl)-calix[4]arenes are able to associate with for-
mation of supercavities, caused by formation of
strong intermolecular hydrogen bonds CH–
OH•••OסP at the upper rim. The present investiga-
tion deals with the preparation of new ␣-hydroxy-
and ␣-aminophosphonic acid diesters and with the
synthesis of calix[4]arenes bearing the fragments of
free ␣-hydroxy- or ␣-aminophosphonic acids.
Calixarene phosphonic acids 24–27 were ob-
tained by reaction of calixarene dialkyl phosphona-
tes 7, 10, 18, and 21 with bromotrimethylsilane (in
dry chloroform), and subsequent alcoholysis of the
silyl esters was obtained with methanol (Scheme 3).
Dialkylphosphoryl-hydroxymethyl-calix[4]arenes
7–13 and dialkylphosphoryl-aminomethyl-calix[4]
arenes 18–23 are colorless crystalline compounds
soluble in many organic solvents. Calix[4]arenes 24–
27 containing the fragments of free ␣-amino(hy-
droxy)phosphonic acids are soluble in polar solvents
(DMSO, DMF, and alcohols). Calix[4]arene mono-
aminophosphonic acids 25 are also soluble in
chloroform.
The syn-orientation of the benzene rings of phos-
phorylated calixarenes 7–13 and 18–27 was demon-
strated by the presence of an AB spin system of non-
equivalent axial and equatorial protons of the
RESULTS AND DISCUSSION
1
ArCH2Ar methylene bridges in the H NMR spectra.
The reaction of formyl compounds with trialkyl
phosphites, which have been developed recently
[16], is a convenient synthetic procedure for intro-
duction of phosphonyl-hydroxymethyl fragments at
the calixarene upper rim [15]. By the interaction of
para-formylcalix[4]arenes 1–6 (cone conformers)
with trialkyl phosphites in 1,4-dioxane solution, sat-
urated with dry hydrogen chloride at room tempera-
ture, calixarenes 7–13 possessing one, two, or four
dialkylphosphoryl-hydroxymethyl moieties at the
upper rim were obtained (Scheme 1).
The most important methods of the synthesis of
␣-aminophosphonous acid derivatives are based on
Pudovik [17], Mannich [18], and Kabachnik-Fields
reactions [19]. The advantages of phosphorylation
using the Pudovik method are high regioselectivity
and stereoselectivity, good yields, and accessibility of
reagents. We used this method for functionalization
of the calixarene upper rim with dialkylphosphoryl-
aminomethyl fragments.
The precursors, para-iminomethylcalixarenes
14–17, were obtained by refluxing stoichiometrical
quantities of formylcalixarenes 1, 2, and 4 with
amines in meta-xylene in the presence of molecular
sieves, which bind the evolved water as described in
the literature [15]. The preparation of dialkylphos-
phoryl-aminomethyl moieties at the upper rim was
performed by reaction of para-iminomethylcalixar-
enes 14–17 with dialkyl phosphites in the presence
of sodium. Unlike the phosphorylation of para-imi-
nodialkoxycalix[4]arenes 14, 16, and 17 in the pres-
ence of an excess of sodium, in the reaction with a
para-iminotetraalkoxycalix[4]arene 15, a catalytic
quantity of sodium is sufficient. Yields of ca-
Phosphorylated dipropoxycalix[4]arenes 9–11,
18, 20–23, and 25–27 adopt the flattened cone con-
formation, characteristic of dialkoxycalix[4]arenes
[2,20]. In the 1H NMR spectra, the signals of OH pro-
tons are found at low field more than 8.00 ppm due
to formation of two strong hydrogen bonds
OH•••OPr between proximal fragments on the mac-
rocyclic lower rim. The distance (Dd) between non-
equivalent axial and equatorial protons of ArCH2Ar
methylene links of calixarenes 9–11, 18, 20–23, and
25–27 in 1H NMR spectra, reflecting the dihedral an-
gles formed by neighboring benzene fragments, are
in the range of 0.54–0.97 ppm. The values of Dd are
characteristic for dialkoxycalix[4]arenes in the flat-
tened cone (C2v symmetry) conformation. In this
conformation, phosphorylated benzene fragments
are forced to a coplanar orientation due to formation
of the intramolecular hydrogen bonds OH•••OPr. Al-
koxylated fragments are nearly perpendicular to the
main molecular plane of the macrocycle. This con-
formation was confirmed by means of a molecular
mechanics calculation (Program PCMODEL) (Fig-
ure 1).
The values Dd 1.24–1.31 ppm for tetraalkoxyca-
lix[4]arenes 7, 8, 12, 13, 19, and 24 indicate the cone
conformation (symmetry C4v) [2]. This conformation
can be considered as a transition structure in a fast
interconversion flattened cone–flattened cone, char-
acteristic of tetraalkoxycalix[4]arenes [21].
An important feature of bis-phosphorylated ca-
lix[4]arenes 9–12, 20–23, 26, and 27 is the presence
of two chiral carbon atoms of methylol or amino-
methyl groups at the upper macrocyclic rim and the
possibility of the formation of d,l-racemic and (or)

60 Solovyov et al.
SCHEME 1
meso-forms in the process of their synthesis (Figure
2).
group takes place. Formation of only one diastereo-
1
isomer of compound 18 is confirmed by the H and
The addition of dialkyl phosphites to CסN
bonds of iminocalix[4]arenes 14–17 is highly stereo-
specific, as previously observed in similar reactions
[22]. In the case of bis-phosphorylation, only one of
two possible diastereomers was obtained. This result
was proved by the fact that only one set of signals in
the 1H and 31P NMR spectra of calixarenes 21 and 22
is present.
31P NMR spectra.
Unlike observations with aminophosphonate de-
rivatives of calixarenes, doubling of signals is ob-
served in the 1H and 31P NMR spectra of bis-hydrox-
yphosphonates. The ratio of intensity of signals in
1
the H NMR spectra is dependent on the size of the
alkyl groups at phosphorus atoms and the conditions
of the reactions. The observed spectral data in bis-
hydroxyphosphonates 9–12 can be explained from
the point of view of the formation of a stereoisomeric
mixture of d,l-racemic and meso-forms. One of the
Analogous stereospecificity in phosphorylation
of monoimino-calix[4]arene 14 containing a chiral
carbon bonded to the nitrogen atom of the imine

Calix[4]arenes Bearing ␣-Amino- or ␣-Hydroxyphosphonic Acid Fragments at the Upper Rim 61
SCHEME 2
diastereomers formed can be isolated by crystalli-
zation [15].
It should be noted, in accordance with molecular
modeling data, that this association is possible only
in the case of the same configuration of the chiral
carbon atoms of the phosphonomethylol fragments
(R ם R or S ם S but not R ם S). The association is
confirmed by CH–OH•••OסP hydrogen bonds at
Derivatives of ␣-hydroxyphosphonic acids can
form dimeric associates caused by intermolecular
hydrogen bonds CH–OH•••OסP [23]. In accordance
with fast atom bombardment (FAB) mass spectra
ם
מ1
([2M] peaks) and IR spectra (associated CH–OH
3310–3360 cm in the IR spectra. A more detailed
groups at 3310–3360 cmמ1), all mono(dialkyl-
phosphoryl-hydroxymethyl) calix[4]arenes 7 and 8
as well as bis(dialkylphosphoryl-hydroxymethyl) ca-
lix[4]arenes 9–11 existing in the stereochemically
rigid flattened cone conformation, with a large dis-
tance (near 13 A) between the opposite phosphorus
atoms, form the CH-OH•••OסP hydrogen bonded
dimers (Figure 3).
The sterochemically flexible cone conformation
of bis or tetrakis(dialkylphosphoryl-hydroxymeth-
yl)tetrapropoxycalix[4]arenes 12 and 13 allows the
formation of two types of associates, with both in-
termolecular (dimeric structure, similar to that
shown in Figure 3) or intramolecular (monomeric
structure, Figure 4) hydrogen bonds.
investigation of association of tetrapropoxycalixar-
enes 7, 8, 12, and 13 is in progress.
In contrast to dialkylphosphoryl-hydroxy-
methyl-calixarenes 7–13, calix[4]arenes 18–23 pos-
sessing dialkylphosphoryl-aminomethyl groups are
unable to form strong CH–NH•••OסP associates
[15]. No dimers were observed in their FAB mass
spectra. Unlike the esters 18–23, the aminophos-
phonic acid 25 forms a dimeric structure caused by
strong intermolecular PסO•••HO–P bonds. This
process was confirmed by the presence of peaks of
the dimer in the FAB mass spectra.
˚
In conclusion, calix[4]arenes bearing dialkyl-
phosphoryl-hydroxymethyl fragments at the macro-
cyclic upper rim, as well as bis(dialkylphosphoryl-

62 Solovyov et al.
SCHEME 3
FIGURE 1 Energy minimized structure of calixarene 10.
hydroxymethyl(aminomethyl))
fragments,
are
pounds with bioactive molecules and their transport
through biomembranes is therefore possible.
similar to calix[4]arenes functionalized with carbox-
ylic [24], acetamide [25], and (thio)urea [25,26]
groups and are able to undergo self-assembly with
formation of dimeric hydrogen bonded associates.
Formation of capsule type complexes of the com-
EXPERIMENTAL
1H NMR and 31P NMR spectra were recorded on a
VXP 300 instrument operating at 300 MHz and 121.5

Calix[4]arenes Bearing ␣-Amino- or ␣-Hydroxyphosphonic Acid Fragments at the Upper Rim 63
FIGURE 2 d,l-Racemic and meso-forms of bis(dialkyl-
phosphoryl-hydroxymethyl)-calixarenes
FIGURE 4 Energy minimized structure of calixarene 12
(S,S-diastereoisomer) (hydrogen atoms are omitted for clar-
ity).
FIGURE 3 Dimeric association of bis(dialkylphosphoryl-hy-
droxymethyl)dipropoxycalixarenes 9–11
5-Bromo-17-formyl-25,26,27,28-
tetrapropoxycalix[4]arene 3
Compound 3 was obtained as a by-product in the
synthesis of diformylcalix[4]arene 5 in accordance
with the method described in Ref. [27d] by the re-
action of the dibromotetrapropoxycalixarene with
butyllithium and DMF. Isolation by column chro-
matography, Rf 0.6 (CH2Cl2/EtOH 10:1). Colorless
crystalline compound: yield 34%, m.p. 130–132ꢀC.
1H NMR (CDCl3), d 1.02 (m, 12H, CH2CH2CH3), 1.98
(m, 8H, CH2CH2CH3), 3.16, 3.23 (two d, 2H ם 2H, J
13.5 Hz, ArCH2 eq), 3.85 (m, 8H, OCH2), 4.44, 4.49
(two d, 2H ם 2H, J 13.5 Hz, ArCH2 ax), 6.42 (s, 2H,
ArH), 6.60–6.77 (m, 6H, ArH), 6.99 (s, 2H, ArH), 9.57
(s, 1H, CHO).
MHz, respectively. The chemical shifts are reported
from internal tetramethylsilane and external 85%
H3PO4 standards. The FAB mass spectra were ob-
tained with a double focusing Kratos MS 50S instru-
ment equipped with a standard FAB source and a DS
90 data system, using m-nitrobenzyl alcohol as a ma-
trix. The melting point determinations were per-
formed on a Boetius apparatus and are uncorrected.
IR spectra were recorded on a spectrometer M-80.
CCl4 for spectroscopy measurements was distilled
˚
over P2O5 and stored over molecular sieves (3A) to
obtain the condition in which water absorption
bands va and vas in this solvent (with thickness of
absorptions layer 10 cm) were absent. 1,4-Dioxane
was distilled over CaH2 and stored over molecular
General Procedure for the Preparation of
Calixarenes 7–13
˚
sieves (3A). Bromotrimethylsilane was freshly dis-
tilled. All reactions were carried out under dry argon.
Purification of compounds 18–23 was achieved by
column chromatography on silica gel (Silufol L 40/
100). Formylcalix[4]arenes 1–6 were synthesized ac-
cording to literature procedures [27]. A detailed pro-
cedure for the preparation of iminocalix[4]arene 17
has been described in the literature [15].
To a suspension of monoformyl-, diformyl-, or tetra-
formylcalixarenes (0.1 mmol) in dioxane (or THF) (5
mL), the trialkyl phosphites (1 mmol, 2 mmol, or 4
mmol, respectively) were added. Gaseous hydrogen
chloride (dried by CaCl2) was bubbled through the
reaction mixture with stirring at room temperature
over a period of 0.5 hours. The resulting clear solu-

64 Solovyov et al.
tion was stirred for 1 hour. The reaction mixture was
evaporated in vacuum to give an oil. The oil was
washed with petroleum ether (or with diethyl ether
in the case of dimethylphosphoryl-hydroxymethyl
derivatives). White powders were obtained and dried
in deep vacuum at room temperature over a period
of 5–10 hours. Yields were 85–90%.
4H, ArCH2eq), 3.66–4.43 (m, 28H, ArCH2ax ם OCH2),
4.80 (m, 4H, PCH), 7.30 (wide s, 8H, ArH). MS (FAB)
ם
m/z; 946[M מ 2H2O–2H P O(OC2H5)2 ם H] , 1258[M
ם
ם H] . Calculated: M 1257.5.
General Procedure for the Preparation of
Iminomethylcalix[4]arenes 14–16
To a suspension of monoformyl- or diformylca-
lix[4]arene (2 mmol) in meta-xylene (40 mL), the
amine (4 mmol or 6 mmol accordingly) was added.
The reaction mixture was refluxed over molecular
5-Diethylphosphoryl-hydroxymethyl-
25,26,27,28-tetrapropoxycalix[4]arene 7
A colorless crystalline compound: yield 85%, m.p.
˚
sieves (3A) for 30 hours. The resulting clear solution
1
134–136ꢀC (cyclohexane). H NMR (CDCl3), d: 1.04
was separated from the molecular sieves and evap-
orated in a vacuum to give a yellow solid. The solid
was washed with hot hexane (60ꢀC). A yellow powder
was obtained and dried in a vacuum (0.05 mm, 2
hours).
(m, 12H, CH2CH2CH3), 1.30 (m, 6H, OCH2CH3), 2.00
(m, 8H, CH2CH2CH3), 3.19 (d, 4H, J 12.9 Hz,
ArCH2eq), 3.90 (m, 10H, OCH2) 4.10 (m, 2H,
OCH2CH3), 4.50 (d, 4H, J 12.9 Hz, ArCH2ax), 4.73 (d,
1H, J 19.8 Hz, CHP), 6.44–7.04 (m, 11H, ArH). 31P
NMR d (CDCl3) 22.05.
5-N-( )-␣-Phenylethylmetylenimino-25,27-
L
dipropoxycalix[4]arene 14
5-Bromo-17-diethylphosphoryl-hydroxymethyl-
A colorless crystalline compound: yield 80%. m.p.
160–165ꢀC. 1H NMR(CDCl3), d: 1.30 (t, 6H, J 7.2 Hz,
CH2CH2CH3), 1.60 (d, 3H, J 7.2 Hz, CHCH3), 2.10 (m,
4H, CH2CH2CH3), 3.38, 3.45 (two d, 2H ם 2H, J 13.2
Hz, ArCH2eq), 3.98 (t, 4H, J 7.2 Hz, OCH2), 4.29, 4.31
(two d, 2H ם 2H, J 13.2 Hz, ArCH2ax), 4.50 (q, 1H, J
7.2 Hz, CHCH3), 6.07 (t, 1H, J 7.2 Hz, ArH), 6.74 (t,
2H, J 7.2 Hz, ArH), 6.93 (m, 3H, ArH), 7.05 (d, 4H, J
7.2 Hz, ArH), 7.33 (t, 2H, J 7.2 Hz, ArH), 7.41 (d, 2H,
J 7.2 Hz, ArH), 7.51 (s, 2H, ArH), 8.22 (s, 1H, OH),
8.23 (s, 1H, OH), 8.69 (s, 1H, CHסN).
25,26,27,28-tetrapropoxycalix[4]arene 8
A colorless crystalline compound: yield 80%, m.p.
1
130–132ꢀC (hexane). H NMR (CDCl3), d 0.93 (m,
12H, CH2CH2CH3), 1.30 (m, 6H, CH2CH3), 1.84 (m,
8H, CH2CH2CH3), 3.07 (d, 4H, J 12.9 Hz, ArCH2eq),
3.67–4.11 (m, 12H, OCH2), 4.37 (d, 4H, J 13 Hz,
ArCH2ax), 4.67 (d, 1H, J 13.8 Hz, CHP), 6.34 (s, 2H,
ArH), 6.45–6.68 (m, 6H, ArH), 6.73, 6.92 (two s, 1H
ם 1H, diastereotopic ArH).
5,17-Bis(diethylphosphoryl-hydroxymethyl)-
25,26,27,28-tetrapropoxycalix[4]arene 12
5-N-tolylmetylenimino-25,26,27,28-
tetrapropoxycalix[4]arene 15
A colorless crystalline compound: yield 90%, m.p.
A colorless crystalline compound: yield 75%, m.p.
160–165ꢀC. 1H NMR(CDCl3), d: 1.04 (m, 12H,
CH2CH2CH3), 1.94 (m, 8H, CH2CH2CH3), 2.38 (s, 3H,
ArCH3), 3.17, 3.26 (two d, 2Hם2H, J 13.2 Hz,
ArCH2eq), 3.80–4.01 (m, 8H, OCH2), 4.47, 4.50 (two
d, 2H ם 2H, J 13.2 Hz, ArCH2ax), 6.52–6.74 (m, 9H,
ArH, NS), 7.10, 7.19 (two d, 2H ם 2H, J 8.1 Hz,
C6H4), 7.28 (s, 2H, ArH, S), 8.23 (s, 1H, CHסN)
1
110–112ꢀC (cyclohexane). H NMR (CDCl3), d: 0.84,
1.02 (two m, 6H ם 6H, OC2HCH3), 1.14 (t, 6H, J 7.2
Hz, CH2CH2CH3), 1.31 (t, 6H, J 7.2 Hz, CH2CH2CH3),
1.83 (m, 8H, CH2CH2CH3), 3.10 (d, 4H, J 13.2 Hz,
ArCH2eq), 3.55–4.40 (m, 16H, OCH2) 4.37 (d, 4H, J
13.2 Hz, ArCH2ax), 4.81, 4.85 (two d, 1H ם 1H, J 12.9
Hz and J 13.5 Hz, PCH), 6.20 (m, 6H, ArH), 7.00–
7.17 (m, 4H, ArH). MS (FAB) m/z; 769[M-H2O–
ם
ם
HPO(OC2H5)2 ם H] , 907[M מ H2O ם H] , 925[M
5,17-Bis-(N-( )-␣-phenylethylmetylenimino)-25,
L
ם
ם H] . Calculated: M 924.0.
27-dipropoxycalix[4]arene 16
A colorless crystalline compound: yield 76%, m.p.
150–153ꢀC. 1H NMR (CDCl3), d: 1.30 (t, 6H, J 7.5 Hz,
CH2CH2CH3), 1.59 (d, 6H, J 6.6 Hz, CHCH3), 2.05 (m,
4H, CH2CH2CH3), 3.44 (d, 4H, J 13.2 Hz, ArCH2eq),
3.98 (t, 4H, J 6.8 Hz, OCH2), 4.28 (d, 4H, J 13.2 Hz,
ArCH2ax), 4.49 (q, 2H, J 6.6 Hz, CHCH3), 6.72 (t, 2H,
J 7.2 Hz, ArH-p NS), 6.92 (d, 4H, J 7.2 Hz, ArH-m
5,11,17,23-Tetrakis(diethylphosphoryl-hydroxy-
methyl)-25,26,27,28-tetrapropoxycalix[4]
arene 13
Colorless crystalline compound: yield 90%, m.p. 80–
1
85ꢀC (cyclohexane). H NMR (CDCl3), d: 0.92–1.40
(m, 36H, CH3), 1.92 (m, 8H, CH2CH2CH3), 3.20 (m,

Calix[4]arenes Bearing ␣-Amino- or ␣-Hydroxyphosphonic Acid Fragments at the Upper Rim 65
NS), 7.22–7.50 (m, 14H, ArH-m S ם C6H5), 8.22 (s,
5,17-Bis(diethylphosphoryl-aminomethyl)-
2H, CHסN), 8.52 (s, 2H, OH).
25,27-dipropoxycalix[4]arene 20
Purification by column chromatography (CHCl3/
C2H5OH 10:1), Rf 0.5. A colorless crystalline com-
pound: yield 65%, m.p. 80–83ꢀC. 1H NMR (CDCl3), d:
0.66, 1.32 (two t, 6H ם 6H, J 7.5 Hz, diastereotopic
OCH2CH3), 1.33 (m, 6H, CH2CH3), 2.01 (m, 4H,
CH2CH2CH3), 2.10 (d, 6H, CHCH3), 3.36 (d, 4H, J
13.0 Hz, ArCH2eq), 3.70, 4.15 (two m, 4H ם 4H, dias-
tereotopic POCH2), 3.97, 3.98 (two t, 2H ם 2H, J 7.5
Hz, diastereotopic OCH2), 4.31 (d, 4H, J 13.0 Hz,
ArCH2ax), 6.35 (m, 2H, PCH), 6.68–7.11 (m, 20H,
ArH), 8.20 (s, 2H, OH). 31P NMR (CDCl3), d 25.7.
General Procedure for the Preparation of
Calixarenes 18–23
To a given dialkyl phosphite (3 mL), sodium (3.2
mmol) was added by portions (with caution). To the
solution of the sodium dialkyl phosphite formed,
monoimino- or diiminodipropoxycalix[4]arenes (0.4
mmol for calixarenes 14 or 0.8 mmol for calixarenes
16–17) were added. (In the case of monoformylca-
lix[4]arene 15, just a catalytic quantity of sodium
was used). The mixture was stirred at room tem-
perature for 3 hours. The reaction was quenched by
addition of water (100 mL). A white precipitate was
filtered off, washed with water, hexane, and diethyl
ether, and purified by column chromatography.
5,17-Bis(dibenzylphosphoryl-aminomethyl)-
25,27-dipropoxycalix[4]arene 23
A colorless crystalline compound: yield 65%. m.p.
96–100ꢀC (cyclohexane). 1H NMR (CDCl3), d; 1.28 (m,
6H, CH2CH3), 2.01 (m, 4H, CH2CH3), 2.17 (s, 6H,
ArCH3), 3.24, 3.29 (two d, 2H ם 2H, J 12.6 Hz dias-
tereotopic ArCH2eq), 3.89 (m, 4H, OCH2), 4.17, 4.23
(two d, 2H ם 2H, J 12.6 Hz diastereotopic ArCH2ax),
4.46, 4.99 (two m, 4H ם 4H, CH2Ph), 4.70 (d, 2H, J
21.6 Hz, PCH), 6.45–6.90 (m, 14H, ArH), 7.16, 7.23
(two s, 2H ם 2H, diastereotopic ArH-m S), 8.28 (s,
2H, O H).31P NMR (CDCl3), d 25.2.
5-Diethylphosphoryl-aminomethyl-25, 27-
dipropoxycalix[4]arene 18
Purification by column chromatography (CHCl3/
C2H5OH 10:1), Rf 0.8. Colorless crystalline com-
pound: yield 60%, m.p. 120–123ꢀC. 1H NMR (CDCl3),
d: 0.85, 1.32 (two d, 3H ם 3H, J 7.5 Hz, diastereo-
topic OCH2CH3), 1.30, 1.31 (two t, 3H ם 3H, J 7.5
Hz, diastereotopic CH2CH3), 1.33 (m, 3H, diaster-
eotopic CHCH3), 2.01 (m, 4H, CH2CH2CH3), 3.32,
3.34 (two d, 2H ם 2H, J 13.2 Hz, ArCH2eq), 3.75, 4.15
(two m, 2H ם 2H, diastereotopic POCH2), 3.96, 3.98
(two t, 2H ם 2H, J 7.5 Hz, OCH2), 4.24, 4.26, 4.28,
4.31 (four d, 4H, J 13.2 Hz, diastereotopic ArCH2ax),
6.30 (d, 1H, J 23 Hz, PCH), 6.80–7.40 (m, 11H, ArH),
8.40 (s, 2H, OH). 31P NMR (CDCl3), d 26.4.
General Procedure for Synthesis of Calixarene
Phosphonic Acids 24–27
To a solution of mono- and diphosphorylated ca-
lix[4]arenes 7, 10, 18, and 21 (0.1 mmol) in 5 mL of
dry chloroform, bromotrimethylsilane (1 and 2
mmol respectively) was added. The reaction mixture
was stirred at room temperature for 30 hours. The
reaction mixture was evaporated under reduced
pressure. An excess of absolute methanol was added
to the residue. The methanol solution was heated at
50ꢀC for 2 hours, and the solvent was evaporated. A
solid residue was dried in vacuum (0.05 mm) for 10
hours.
5-Diethylphosphoryl-aminomethyl-25,26,27,28-
tetrapropoxycalix[4]arene 19
Purification by column chromatography (CHCl3/
C2H5OH 5:1), Rf 0.6. Colorless crystalline compound:
yield 60%, m.p. 106–109ꢀC. 1H NMR (CDCl3), d: 0.80–
1.40 (m, 18H, diastereotopic OCH2CH3 ם CH2CH3),
1.95 (m, 8H, CH2CH2CH3), 2.18 (s, 3H, ArCH3), 3.12,
3.13, 3.16, 3.19 (four d, 4H, J 12.3 Hz, diastereotopic
ArCH2eq), 3.69, 4.02 (two m, 4H ם 4H, diastereotopic
OCH2), 3.89, 4.20 (two m, 2H ם 2H, diastereotopic
POCH2), 4.42, 4.45, 4.47, 4.49 (four d, 4H, J 12.3 Hz,
diastereotopic ArCH2ax), 4.75, 4.80 (two d, 1H, J 21
Hz, PCH), 5.82 (d, 1H, J 8.7 Hz, NH), 6.20 (m, 5H,
ArH), 6.63, 6.97 (two d, 2H ם 2H, J 8.1 Hz, C6H4),
6.65 (m, 1H, ArH), 6.89 (t, 1H, J 7.5 Hz, ArH), 7.10
(d, 2H, 7.5 Hz, ArH), 7.14, 7.20 (two s, 1H ם 1H,
diastereotopic ArH) 31P NMR (CDCl3), d 24.14.
5-Dihydroxyphosphoryl-hydroxymethyl-
25,26,27,28-tetrapropoxycalix[4]arene 24
Colorless crystalline compound: yield 85%, m.p.
1
250–260ꢀC (dec.). H NMR (DMSO-d6), d: 0.95 (m,
12H, CH2CH2CH3), 1.93 (m, 8H, CH2CH2CH3), 3.07
(d, 4H, J 13 Hz, ArCH2eq), 3.67–3.84 (m, 8H, OCH2),
4.37 (d, 4H, ArCH2ax), 6.33–6.68 (m, 9H, ArH), 6.73,
6.93 (two s, 1H ם 1H, diastereotopic ArH). 31P NMR
(CD3CN), d 16.7.

66 Solovyov et al.
hoven, J. P. M.; Engbersen, J. F. S.; Reinhoudt, D. N.
Angew Chem Int Ed Engl 1996, 35, 1090–1092. (c)
Hamann, B. C.; Shimisu, K. D.; Rebek, J. Angew
Chem Int Ed Engl 1996, 35, 1326–1329.
5-Dihydroxyphosphoryl-N-( )␣-phenylethyl-
aminomethyl-25,27-dipropoxycalix[4]arene 25
A colorless crystalline compound: yield 85%. 1H
L
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NMR (CDCl3), d: 0.98 (m, 9H, CH3CH
ם
CH2CH2CH3), 1.65 (m, 4H, CH2CH2CH3), 3.10 (d, 4H,
12.6 Hz, ArCH2eq), 3.16 (q, 1H, 7.2 Hz, CH3CH), 3.67
(m, 4H, OCH2), 3.97 (m, 4H, ArCH2ax), 6.4–7.2 (m,
16H, ArH), 8.00 (s, 1H, OH), 8.20, 8.60 (two s, 1H ם
1H, POH), 10.0 (s, 1H. OH)31P NMR (CDCl3), d 14.4
ם
MS (FAB) m/z; 640[M - HP O(OH)2 ם H] , 723[M ם
ם
ם
H] , 1444[2MםH] . Calculated: M 722.0.
5,17-Bis(dihydroxyphosphoryl-N-tolylamino-
methyl)-25,27-dipropoxycalix[4]arene 26
A colorless crystalline compound: yield 88%. 1H
NMR (DMSO-d6), d: 1.70 (m, 6H, CH2CH2CH3), 1.95
(m, 4H, CH2CH2CH3), 2.07 (s, 6H, ArCH3), 3.50, 3.60
(two d, 2H ם 2H, 12.6 Hz, ArCH2eq), 3.94 (m, 4H,
OCH2) 4.10, 4.14 (two d, 2H ם 2H, 12.6 Hz, ArCH2ax),
7.10–7.88 (m, 18H, ArH), 9.44–9.56 (two s, 1H ם 1H,
OH). 31P NMR (DMSO-d6), d 16.7.
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5,17-Bis(dihydroxyphosphorylhydroxymethyl)-
25,27-dipropoxycalix[4]arene 27
A colorless crystal compound: yield 85%, m.p.
1
250–260 ꢀC (dec.). H NMR (DMSO-d6), d: 1.35 (m,
6H, CH2CH2CH3), 2.05 (m, 4H, CH2CH2CH3), 3.35 (d,
4H, J 13 Hz, ArCH2eq), 3.90 (d, 4H, OCH2) 4.20 (d,
4H, J 13 Hz ArCH2ax), 6.65 (m, 2H, ArH), 6.95 (m,
4H, ArH), 7.10 (m, 4H, ArH). 31P NMR (DMSO-d6),
ם
d 19.7. MS (ES) m/z; 651[M מ HP O(OH)2 , 693[M
ם
ם
מ 2H2O] , 729[M] . Calculated M 728.0.
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